Human Pharmaceuticals in Environment

8/17/2019 Human Pharmaceuticals in Environment

1/302

For further volumes:

http://www.springer.com/series/7360

Emerging Topics in Ecotoxicology

Principles, Approaches and Perspectives

Volume 4

Series Editor

Lee R. Shugart

L.R. Shugart and Associates, Oak Ridge, TN, USA

http://www.springer.com/series/7360http://www.springer.com/series/7360http://www.springer.com/series/7360


2/302


3/302

Bryan W. Brooks Duane B. HuggettEditors

Human Pharmaceuticalsin the Environment

Current and Future Perspectives


4/302

Editors

Bryan W. BrooksBaylor UniversityWaco, Texas, USA

Duane B. HuggettUniversity of North TexasDenton, Texas, USA

ISSN 1868-1344 ISSN 1868-1352 (electronic)ISBN 978-1-4614-3419-1 ISBN 978-1-4614-3473-3 (eBook)

DOI 10.1007/978-1-4614-3473-3Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 201293197

© Springer Science+Business Media, LLC 2012All rights reserved. This work may not be translated or copied in whole or in part without the writtenpermission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use inconnection with any form of information storage and retrieval, electronic adaptation, computer software,or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they

are not identified as such, is not to be taken as an expression of opinion as to whether or not they aresubject to proprietary rights.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)


5/302

v

Perspectives on Human Pharmaceuticals in the Environment ................... 1

Bryan W. Brooks, Jason P. Berninger, Alejandro J. Ramirez,

and Duane B. Huggett

Environmental Risk Assessment for Human Pharmaceuticals:

The Current State of International Regulations .......................................... 17

Jürg Oliver Straub and Thomas H. Hutchinson

Regulation of Pharmaceuticals in the Environment: The USA .................. 49

Emily A. McVey

Environmental Fate of Human Pharmaceuticals ......................................... 63

Alistair B.A. Boxall and Jon F. Ericson

Environmental Comparative Pharmacology: Theory

and Application ............................................................................................... 85

Lina Gunnarsson, Erik Kristiansson, and D.G. Joakim Larsson

A Look Backwards at Environmental Risk Assessment:

An Approach to Reconstructing Ecological Exposures ............................... 109

David Lattier, James M. Lazorchak, Florence Fulk, and Mitchell Kostich

Considerations and Criteria for the Incorporation of

Mechanistic Sublethal Endpoints into Environmental

Risk Assessment for Biologically Active Compounds .................................. 139

Richard A. Brain and Bryan W. Brooks

Human Health Risk Assessment for Pharmaceuticals in the

Environment: Existing Practice, Uncertainty, and Future Directions ....... 167

E. Spencer Williams and Bryan W. Brooks

Contents


6/302

vi Contents

Wastewater and Drinking Water Treatment Technologies ......................... 225

Daniel Gerrity and Shane Snyder

Pharmaceutical Take Back Programs ........................................................... 257

Kati I. Stoddard and Duane B. Huggett

Appendix A. Take Back Program Case Studies ........................................... 287

Index ................................................................................................................. 297


7/302

vii

Jason P. Berninger Department of Environmental Science, Center for Reservoir

and Aquatic Systems Research, Institute of Biomedical Studies, Baylor University,

Waco, TX 76798, USA

Office of Research and Development, National Health and Environmental Effects

Research Laboratory, U.S. Environmental Protection Agency, Duluth, MN 55804, USA

Alistair B.A. Boxall Environment Department, University of York, Heslington,

York YO10 5DD, UK

Richard A. Brain Ecological Risk Assessment, Syngenta Crop Protection LLC,

Greensboro, NC 27409, USA

Bryan W. Brooks Department of Environmental Science, Center for Reservoir

and Aquatic Systems Research, Institute of Biomedical Studies, Baylor University,

Waco, TX 76798, USA

Jon F. Ericson Pfizer Global Research and Development, Worldwide PDM,

Environmental Sciences, MS: 8118A-2026, Groton, CT 06340, USA

Florence Fulk National Exposure Research Laboratory, Ecological ExposureResearch Division, US Environmental Protection Agency, Office of Research and

Development, Cincinnati, OH 45268, USA

Daniel Gerrity Water Quality Research and Development Center, Southern

Nevada Water Authority, River Mountain Water Treatment Facility, Henderson,

NV 89015, USA

Lina Gunnarsson Department of Neuroscience and Physiology, Institute of

Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg,

405 30 Göteborg, Sweden

Duane B. Huggett Department of Biological Sciences, University of North Texas,

Denton, TX 76203, USA

Contributors


8/302

viii Contributors

Thomas H. Hutchinson CEFAS Weymouth Laboratory, Centre for Environment,

Fisheries and Aquaculture Sciences, Weymouth, Dorset DT4 8UB, UK

Mitchell Kostich National Exposure Research Laboratory, Ecological Exposure

Research Division, US Environmental Protection Agency, Office of Research andDevelopment, Cincinnati, OH 45268, USA

Erik Kristiansson Department of Neuroscience and Physiology, Institute of



Department of Zoology, University of Gothenburg, 405 30 Göteborg, Sweden

D.G. Joakim Larsson Department of Neuroscience and Physiology, Institute of



David Lattier National Exposure Research Laboratory, Ecological Exposure

Research Division, US Environmental Protection Agency, Office of Research and

Development, Cincinnati, OH 45268, USA

James M. Lazorchak National Exposure Research Laboratory, Ecological

Exposure Research Division, US Environmental Protection Agency, Office of

Research and Development, Cincinnati, OH 45268, USA

Emily A. McVey Office of Pharmaceutical Science, Center for Drug Evaluation

and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993,

USA

WIL Research, 5203DL ’s-Hertogenbosch, The Netherlands

Alejandro J. Ramirez Mass Spectrometry Center, Mass Spectrometry Core

Facility, Baylor University, Baylor Sciences Building, Waco, TX 76798, USA

Shane Snyder Chemical and Environmental Engineering, University of Arizona,

Tucson, AZ 85721, USA

Jürg Oliver Straub F.Hoffmann-La Roche Ltd, Group SHE, LSM 49/2.033,Basle CH-4070, Switzerland

Kati I. Stoddard Department of Biological Sciences, University of North Texas,

Denton, TX 76203, USA

E. Spencer Williams Department of Environmental Science, Institute of

Biomedical Studies, Center for Reservoir and Aquatic Systems Research, Baylor

University, Waco, TX 76798-7266, USA


9/302

1B.W. Brooks and D.B. Huggett (eds.), Human Pharmaceuticals in the Environment:

Current and Future Perspectives, Emerging Topics in Ecotoxicology 4,

DOI 10.1007/978-1-4614-3473-3_1, © Springer Science+Business Media, LLC 2012

Background

Human interaction with the environment remains one of the most pervasive facets

of modern society. Whereas the anthropocene is characterized by rapid popula-

tion growth, unprecedented global trade and digital communications, energy

security, natural resource scarcities, climatic changes and environmental quality,

emerging diseases and public health, biodiversity and habitat modifications are

routinely touted by the popular press as they canvas global political agendas and

scholarly endeavors. With a concentration of human populations in urban areas

B.W. Brooks (*)

Department of Environmental Science, Center for Reservoir and Aquatic Systems Research,

Institute of Biomedical Studies, Baylor University, One Bear Place, #97266,

Waco, TX 76798, USA

e-mail: [email protected]

J.P. Berninger

Department of Environmental Science, Center for Reservoir and Aquatic Systems Research,Institute of Biomedical Studies, Baylor University, One Bear Place, #97266,

Waco, TX 76798, USA

National Health and Environmental Effects Research Laboratory, National Research Council

Research Associates Program, Office of Research and Development, U.S. Environmental

Protection Agency, 6201 Congdon Boulevard, Duluth, MN 55804, USA


A.J. Ramirez

Mass Spectrometry Center, Mass Spectrometry Core Facility, Baylor University,

Baylor Sciences Building, One Bear Place, #97046, Waco, TX 76798, USA

e-mail: [email protected]. Huggett

Department of Biological Sciences, University of North Texas,

1155 Union Circle, #305220, Denton, TX 76203, USA


Perspectives on Human Pharmaceuticals

in the Environment

Bryan W. Brooks, Jason P. Berninger, Alejandro J. Ramirez,

and Duane B. Huggett


10/302

2 B.W. Brooks et al.

unlike any other time in history, the coming decades will be defined by “A New

Normal,” as proposed by Postel [ 1 ], where the interplay among sustainable

human activities and natural resource management will inherently determine the

regional fates of human societies.

In recent years, few topics have captured the public’s attention like the pres-

ence of human pharmaceuticals in environment. Fish on Prozac [ 2, 3 ]. Male fish

becoming female [ 4, 5 ]? Drugs found in drinking water [ 6, 7 ]. India’s drug

problem [ 8 ]. Chances are you have seen these headlines or read related reports.

Pharmaceuticals and trace levels of other contaminants (e.g., antibacterial agents,

flame retardants, perfluorinated surfactants, harmful algal toxins) are increasingly

reported in freshwater and coastal ecosystems. In the developed world, many of

these chemicals are released at very low levels (e.g., parts per trillion) from waste-

water effluent discharges to surface and groundwaters. But why were citizens so

engaged by stories about fish on Prozac [ 3 ] and drugs in drinking water [ 7 ]?Because pharmacotherapy is now entrenched in everyday life, a realization that

common drugs were found in the water we drink or the fish we eat likely produces

a boomerang effect, where our daily reliance on well-accepted therapies was con-

cretely linked in a new way with their potential consequences to the natural world.

On an increasingly urban planet, pharmaceutical residues and traces of other

contaminants of emerging concern represent signals of the rapidly urbanizing

water cycle and harbingers of the “New Normal.”

Over the past 2 decades the implications of endocrine disruption and modula-

tion have permeated public consciousness, scientific inquiry, regulatory frame-works, and management decisions in the environmental and biomedical sciences.

Publication of Colburn, Dumanoski, and Myers’ “Our Stolen Future [ 9 ],” which

is often referred to as the second coming of Rachel Carson’s “Silent Spring [ 10 ],”

stimulated the public, scientific, and regulatory attention given to endocrine dis-

ruptors and ultimately influenced the environmental studies of human pharma-

ceuticals [ 11 ]. For example, human reproductive developmental perturbations

elicited by the estrogenic human pharmaceutical diethylstilbestrol and feminiza-

tion of male fish exposed to municipal effluent discharges represent examples of

causal relationships among endocrine active substances and biologically importantadverse outcomes [ 12 ].

In the late 1990s, research in the area of endocrine disruption was taking off,

particularly to identify constituents of effluents or other environmental matrices that

were potentially responsible for endocrine perturbations in wildlife and humans.

Because many xenoestrogens are present in effluent discharges, initial investiga-

tions in the UK employed toxicity identification evaluation studies to fractionate

and identify causative components of the complex mixtures inherent with effluents

[ 13 ]. At the same time in the USA, Arcand-Hoy et al. [ 14 ] highlighted the impor-

tance of considering human estrogen agonist and veterinary androgen agonist phar-maceuticals as potential causative toxicants from point and nonpoint source

effluents. Also in 1998, two of the first review papers on pharmaceuticals in the

environment, by Halling-Sorensen et al. [ 15 ] and Ternes [ 16 ], appeared in the litera-

ture. In 1999, another review paper, by Daughton and Ternes [ 17 ], considered


11/302

3Perspectives on Human Pharmaceuticals in the Environment

Pharmaceuticals and Personal Care Products (PPCP) in the environment and by

doing so coined the PPCP acronym, which remains pervasive. Subsequently, a pre-

cipitous number of workshops, symposia, special meetings, and publications related

to pharmaceuticals in the environment have occurred. For example, Fig. 1 describescitation frequencies of just the Halling-Sorensen et al. [ 15 ], Ternes [ 16 ], and

Daughton and Ternes [ 17 ] papers as surrogates for the trajectory of scientific inquiry

in this important area of environmental science and public health.

Some of the most important developments related to pharmaceuticals in the envi-

ronment included special issues of Toxicology Letters in 2002 and 2003, Pellston

workshops by the Society of Environmental Toxicology and Chemistry (SETAC) on

human pharmaceuticals (in 2003 [ 18 ]) and veterinary medicines (in 2007 [ 19 ]),

formation of the SETAC Pharmaceuticals Advisory Group (in 2005; http://www.

setac.org/node/34 ) and the Water Environment Federation’s MicroconstituentsCommunity of Practice ( http://www.wef.org ), International Conferences on the

Occurrence, Fate, Effects, and Analysis of Emerging Contaminants in the

Environment (e.g., htpp://www.EmCon2011.com ), the International Water

Association’s MicroPol conferences (e.g., htpp://www.micropol2011.org ), and a

special issue of Environmental Toxicology and Chemistry entitled “Pharmaceuticals

and Personal Care Products in the Environment” in 2009. Following an editorial by

Brooks et al. [ 20 ] entitled “Pharmaceuticals and Personal Care Products: Research

Needs for the Next Decade,” an international workshop entitled “Effects of

Pharmaceuticals and Personal Care Products in the Environment: What are the BigQuestions?” was held by Health Canada/SETAC in April 2011 [ 21 ]. In 2012, the

SETAC Pharmaceutical Advisory Group is planning another Pellston conference on

antimicrobial resistance, which represents a major threat to global public health.

Though the information in this timely area continues to rapidly expand, it appears

Year

1998 2000 2002 2004 2006 2008 2010

R e l a t i v e C u m u l a t i v e F r e q u e n c y o f C i t a t i o n s

0.0

0.2

0.4

0.6

0.8

1.0

C u m u l a t i v e F r e q u e n c y o f C i t a t i o n s

0

500

1000

1500

2000

2500

Fig. 1 Representative increase in peer-reviewed publications related to pharmaceuticals in the

environmental through 2010, summarized by the cumulative and relative cumulative citation

frequency of early review papers by Halling-Sorensen et al. [ 15 ], Ternes [ 16 ], and Daughton and

Ternes [ 17 ]. Citation information from Web of Knowledge

http://www.setac.org/node/34http://www.setac.org/node/34http://www.wef.org/http://www.wef.org/http://htpp//www.EmCon2011.comhttp://htpp//www.micropol2011.orghttp://htpp//www.micropol2011.orghttp://htpp//www.EmCon2011.comhttp://www.wef.org/http://www.setac.org/node/34http://www.setac.org/node/34


12/302


critically important to now consider the lessons learned from the study of human

pharmaceuticals in the environment and formulate directions for future efforts.

Environmental Analysis and Exposure

To date, the majority of information for human pharmaceuticals in the environment

is related to occurrence in various environmental matrices, which largely accounts

for publication trends summarized in Fig. 1 . Perhaps the most influential paper on

occurrence was published by Kolpin et al. [ 22 ]. In 2002, this landmark article pro-

vided the first national reconnaissance study of a variety of contaminants of emerg-

ing concern, including a number of pharmaceuticals, in water [ 22 ] and promises to

be the most heavily cited paper published in the history of the journal EnvironmentalScience & Technology . In Table 1 , we provide an overview of the representative

literature related to the environmental analysis and occurrence of pharmaceuticals

in the environment. Instead of performing an exhaustive survey and synthesis here,

we instead relay some perspectives on environmental analysis and refer readers to

the recent review of occurrence information for human pharmaceuticals by Monteiro

and Boxall [ 23 ].

Table 1 Representative recent reviews on pharmaceutical analysis in various environmental

matricesTarget analytes Matrix Type of review

Pharmaceuticals Water Analytical methods [ 64 ], multiresidue

methods [ 65 ], LC–MS/MS methods [ 66 ],

basic pharmaceuticals [ 67 ], antibiotics

[ 68 ], anti-inflammatory drugs [ 69 ],

recent advances [ 70 ]

Solidsa LC–MS/MS [ 71 ], tetracycline antibiotics [ 72 ]

Water, solids Analytical methods [ 73 ], LC–MS/MS

methods [ 74 ]

Conventional and/orcontaminants of

emerging concern,

including

pharmaceuticals

Water Analytical methods [ 75, 76 ]Water, solids LC–MS in environmental analysis [ 77 ]

Various environmental

matrices

Analytical methods [ 78, 79 ], methods

applied to fate [ 80 ], environmental mass

spectrometry [ 81 ], recent advances [ 82 ]

Pharmaceuticals

and/or degradation

products

Water Advanced MS techniques [ 83 ], LC–MS

methods [ 84 ], methods applied to fate

and removal [ 85 ]

Various environmental

matrices

Mass spectrometry [ 86 ], analytical problems

and sample preparation [ 87 ]

Other reviews relatedto pharmaceutical

analysis and

general occurrence

information

Multivariate analysis [ 88, 89 ], samplingand/or extraction [ 90– 94 ], chiral analysis

[ 95 ], general occurrence [ 23 ], biological

tissues [ 28, 29, 96 ]

a Sediment, biosolids and soil


13/302


Gas chromatography–mass spectrometry (GC–MS) was the primary analytical

tool used to assess the environmental occurrence of PPCPs in initial studies (Table 1 ).

The popularity of GC–MS in early work was due to its widespread availability and

historical use in contract service laboratories for historical industrial chemical

contaminants. The availability of electron-impact spectral libraries was initially

important, as they increased confidence in analyte identification. Further, the dis-

tinctive nonpolar operating range of GC–MS was consistent with analysis of most

personal care products (PCPs). In contrast, the use of GC–MS for analysis of phar-

maceuticals, which are relatively polar compared to most PCPs, typically requires

derivatization prior to analysis. For example, Brooks et al. [ 3 ] employed GC–MS

with derivatization for initial identification of the antidepressants sertraline and

fluoxetine in fish tissue. However, derivatization reactions are often unpredictable

for complex samples and can limit the quality of quantitative data. Consequently,

liquid chromatography–mass spectrometry (LC–MS) has become the technique ofchoice for analyzing pharmaceuticals in environmental samples.

Numerous studies have demonstrated the distinct advantages of LC–MS for

analysis of pharmaceuticals (Table 1 ). LC–MS enables identification and

quantification without derivatization and typically results in lower detection limits

(below 1 ng/L and 1 ng/g for liquid and solid samples, respectively) and better

precision than comparable GC–MS methodologies. In environmental applications,

LC is typically combined with tandem MS (or MS/MS) to promote enhanced

selectivity and sensitivity for target analytes. In a routine MS/MS analysis, a

molecular ion is selected and subsequently fragmented to produce one or moredistinctive product ions that enable both qualitative and quantitative monitoring.

Recently introduced ultraperformance liquid chromatography (UPLC) provides a

novel approach to chromatographic separation. UPLC differs from regular LC by

the implementation of chromatographic columns with smaller particle diameters

(i.e., sub-2-m m particles), which generates elevated back pressures and narrower

chromatographic peaks. The overall effect is resolved peaks in shorter periods of

time with increased sensitivity. UPLC requires fittings and pumps designed to sup-

port high back pressures, which increases the price of the LC system. An important

feature of UPLC is the need of a fast detector to account for small peak widths(ca. 10 s). In other words to acquire enough data points through chromatographic

peaks, selected mass spectrometer need to collect data points at high sampling

rates. Q-TOF mass spectrometers are often coupled with UPLC systems due to

their fast sampling rates. It is important to note, however, that LC–MS is not exempt

from limitations. One of the limitations of LC–MS is that atmospheric pressure

ionization (API) processes are influenced by coextracted matrix components.

Matrix effects typically result in suppression or less frequent enhancement of ana-

lyte signal. There have been a number of methods proposed to compensate for

matrix effects, including the method of standard addition, surrogate monitoring,and isotope dilution (Table 1 ). Although isotope dilution is the most highly recom-

mended approach for analysis of human pharmaceuticals in environmental matri-

ces, isotopically labeled standards are not always readily available for these target

analytes. A further limitation is the paucity of available isotopically labeled standards


14/302


for therapeutic metabolites. An alternative approach involves the use of an

appropriate internal standard (i.e., a structurally similar compound expected to

mimic the behavior of a target analyte(s)) with or without matrix-matched calibra-

tion. However, a given internal standard is typically effective over a limited reten-

tion time window. Accordingly, the use of more than one internal standard is

recommended to compensate for matrix effects throughout the chromatographic

run. Finally, it is important to point out that strategies to compensate for matrix

effects should take into account the variability of matrix within each set of samples

to be analyzed (e.g., surface water, effluent, sediment, fish tissue).

Due to potential regulatory implications of human pharmaceuticals in the envi-

ronment, environmental analyses typically include rigorous quality assurance and

quality control (QA/QC) metrics to confirm reliability of analytical data. Initial

method validation provides essential performance parameters, such as method

recoveries, precision, and limits of detection (LODs). Recurring analysis of qualitycontrol (QC) samples (e.g., method blanks, matrix spikes, laboratory control sam-

ples) is important to verify performance of the method over time, and to assess

potential matrix effects. Considering the unpredictable nature of matrix interference

in LC–MS analysis and the lack of effective strategies to deal with this difficulty, it

has become imperative to use QA/QC data to document and qualify analytical

results for human pharmaceuticals in environmental matrices. This is particularly

important when reporting concentrations at or near the limit of detection for a given

analytical method.

In this volume, an overview of global environmental regulatory activities rele-vant to human pharmaceuticals is provided in Chaps. 2 and 3 . In Chap. 4 , Boxall

and Ericson examine important considerations for understanding the environmental

fate of therapeutics. Below we provide some perspectives on bioaccumulation and

effects of human pharmaceuticals in the environment.

Environmental Bioaccumulation and Effects

Though the potential for uptake of veterinary medicines by animals reared in aqua-

culture were understood for some time (see [ 24, 25 ]), Boxall et al.’s [ 26 ] study of

the uptake of veterinary medicines from soils to plants highlighted the importance

of considering potential accumulation of human medicines in terrestrial organisms

because biosolids and effluents from wastewater treatment plants can be applied

to agricultural fields. Such observations are particularly relevant for antibiotics.

In fact, developing an understanding of the influences of human antibiotics and

antimicrobial agents on antibiotic resistance was recently identified as critical areas

of research need for environmental science and public health [ 21 ].In aquatic systems, Larsson et al. [ 27 ] likely provided the first report of bioac-

cumulation of a human pharmaceutical, 17a -ethinylestradiol, in bile of fish exposed

to Swedish effluent discharges. Brooks et al.’s [ 3 ] findings of the antidepressants

fluoxetine and sertraline (and their primary metabolites) in brain, liver, and muscle

http://dx.doi.org/10.1007/978-1-4614-3473-3_2http://dx.doi.org/10.1007/978-1-4614-3473-3_3http://dx.doi.org/10.1007/978-1-4614-3473-3_4http://dx.doi.org/10.1007/978-1-4614-3473-3_4http://dx.doi.org/10.1007/978-1-4614-3473-3_3http://dx.doi.org/10.1007/978-1-4614-3473-3_2


15/302


tissues of three fish species from an effluent-dominated stream (a.k.a. fish on

Prozac) appear to represent the second report in the literature of accumulation of

human pharmaceuticals in wildlife and the first observation from North America.

Such observations stimulated research related to the accumulation and effects of

human pharmaceuticals in the environment and subsequently shaped the National

Pilot Study of PPCPs in Fish Tissue by the US Environmental Protection Agency

[ 28 ] . This study by Ramirez et al. [ 28 ] provided the first evidence of bioaccumula-

tion of a number of human pharmaceuticals in fish collected across a broad geo-

graphic area. A summary of research on bioaccumulation of pharmaceuticals in

aquatic organisms recently highlighted the need to understand thresholds of drug

accumulation associated with adverse effects [ 29 ] . Unfortunately, an understand-

ing of human pharmaceuticals accumulating in terrestrial wildlife is poorly under-

stood [ 20 ] but has been recently identified as a major research question [ 21 ].

Several recent publications have started to further our understanding of the biocon-centration/bioaccumulation potential of pharmaceuticals in a laboratory setting, as

well as publications aimed at understanding pharmaceutical metabolism in wildlife

and its role in the accumulation of drugs [ 30– 39 ] . Below we introduce important

considerations for understanding relationships between pharmaco(toxico)kinetics

and -dynamics of human medications in aquatic and terrestrial organisms. A more

thorough examination of comparative pharmacological approaches for environmental

applications is provided by Gunnarsson et al. in Chap. 5.

Understanding the environmental risks posed by historical contaminants has

been challenged by the paucity of toxicity information available for most industrialchemicals [ 40 ]. In the case of human pharmaceuticals, however, intensive investiga-

tions occur prior to distribution, which yields a wealth of pharmacological and toxi-

cological data compared to other industrial contaminants. To illustrate available

data, Table 2 provides a summary of common characteristics for hundreds of phar-

maceuticals. During the design of therapeutics, careful consideration is given to

target-specific biomolecules (e.g., receptors, enzymes) and pathways to elicit

beneficial outcomes. Because side effects are not desirable and large margins of

safety (relationship between therapeutic and toxic doses) are ideal, pharmaceutical

development often results in therapeutics with relative well-understood mecha-nisms/modes of actions (MOAs) and very low acute toxicity in mammals. For

example, a recent study predicted that less than 8% of all pharmaceuticals are

expected to be classified as highly acutely toxic to rodent models [ 41 ]. Similarly,

Berninger and Brooks [ 41 ] predicted that less than 6% of all pharmaceuticals are

acutely toxicity to fish below 1 mg/L.

As noted previously, concentrations of individual human pharmaceuticals in

surface water of developed countries rarely exceed parts per billion levels; thus,

limited acute toxicity is expected in surface waters of the developed world.

Unfortunately, most studies to date have only examined acute toxicity in standardaquatic organisms [ 42 ] . However, chronic adverse responses resulting from thera-

peutic MOAs are more likely to be observed in the environment [ 41 ] , particularly

in systems with instream flows dominated by continuous release of effluent dis-

charges [ 43 ] leading to longer effective exposure durations [ 11 ]. Early investigators

http://dx.doi.org/10.1007/978-1-4614-3473-3_5http://dx.doi.org/10.1007/978-1-4614-3473-3_5


16/302


T a b l e 2

A s u m m a r y o f t h e m i n i m u m a n d m

a x i m u m v a l u e s a n d 1 0 t h ,

5 0 t h , a

n d 9 0 t h c e n t i l e s o f c o m m o n p r o p e r t i e s a s s o c i a t e d w i t h p h a r m a c e u t i c a l s

M W

l o g

P

L D

5 0

C m a x

A T R

C l

T ½

V d

A q E T

M i n

6 . 9

4

− 9 . 4

0 . 0

0 0 7 5

7 . 5 × 1 0

− 6

1 . 6

0 . 0

0 2 9

0 . 0

3 3

0 . 0

3 5

8 . 4 × 1 0 −

1 0

C e n t i l e s

1 0 t h

1 6 4

− 0 . 9

5

7 7

0 . 0

0 1 7

9 7

0 . 4

9

0 . 7

7

0 . 1

5

2 . 9 × 1 0 −

5

5 0 t h

3 4 6

2 . 0

3

9 7 1

0 . 1

3 0 0

8 , 1

2 7

3 . 7

1

5 . 0

1

1 . 0

3

0 . 0

4 4 6

9 0 t h

7 3 2

5 . 0

1

1 2 , 2

8 3

9 . 9

1

6 8 1 , 6

5 7

2 7 . 9

3 2 . 6

6 . 9

6

6 9 . 4

M a x

1 4 5 , 7

8 1

8 . 6

5 6 , 0

0 0

3 3 0

4 . 7 × 1 0 8

1 , 0

7 0

8 7 , 6

0 0

2 , 3

4 8

9 . 1 × 1 0 9

n

1 , 0

4 2

7 9 7

1 , 0

3 5

8 3 2

7 4 1

9 3 6

9 7 9

9 4 4

8 3 1

M W m o l e c u l a r w e i g h t ( g / m o l ) ; l o g P o c t a n o l

– w a t e r p a r t i t i o n i n g c o e f fi c i e n t ; L

D 5

0 m e d i a n o r a l l e t h a l d o s e f o r r a t m o d e l ( m g / k g ) ; C

m a x

h u m a n p

e a k p l a s m a

c o n c e n t r a t i o n ( o r t h e r a p e u t i c d o s e ; m g

/ m L ) ; A T R a c u t e t o t h e r a p e u t i c r a t i o m a r g i n o f s a f e t y a n a l o g ( L D

5 0

/ C m a

x ; s e e B e r n i n g e r a n d B r o o k s [ 4 1 ] ) ; C l c l e a r -

a n c e r a t e ( m

g / m i n / k g ) ; T

½ h

a l f - l i f e o f e l i m i n a t i o n ( h o u r ) ; V

d a p p a r e n t v o l u m e o f d i s t r i b u t i o n ( L / k g ) ; A q E T i s

t h e a q u e o u s e f f e c t t h r e s h o l d ( m

g / L ) w h e r e

fi s h p l a s m a B C F / C

m a x

= a q u a t i c e x p o s u r e c o n c e n t r a t i o n a t t h e p o i n t i n w h i c h C

m a x

= fi s h p l a s m a c o n c e n t r a t i o n a n d fi s h p l a s m a B C F × e

x p o s u r e

c o n c e n t r a -

t i o n = fi s h p l a s m a c o n c e n t r a t i o n [ 2 9 ]


17/302


recognized the importance of leveraging mammalian pharmacological safety data

to help understand various pharmaceutical effects in the environment, because

many MOAs of human therapeutics appear to be evolutionarily conserved, particularly

in vertebrates [ 14, 44– 46 ].

In 2003, Huggett et al. [ 47 ] proposed a screening approach to identify pharma-

ceuticals in water that may result in fish plasma levels (or internal doses)³ human

therapeutic levels (e.g., C max

). Huggett’s plasma model was based on three core

assumptions: (1) Evolutionary conservation of structure and function of drug targets

among mammals and fish species; (2) Internal fish doses approaching mammalian

C max

levels would result in similar therapeutic outcomes; and (3) A gill uptake model

[ 48 ] for predicting rainbow trout plasma concentrations following waterborne expo-

sure to nonionizable chemicals [ 48 ]. Subsequently, several recent studies have

employed the Huggett et al. plasma model approach [ 49– 51 ] or conceptually similar

variations to account for ionization influences on bioavailability [ 29, 52, 53 ]. Ofparticular importance, Valenti et al. [ 53 ] recently provided an independent valida-

tion of the Huggett et al. [ 47 ] plasma model when ionization of the weak base ser-

traline [ 54 ] and an alternative gill uptake model [ 48 ] was considered. Valenti et al.

[ 53 ] also employed an adverse outcome pathway (AOP) design [ 55 ], which included

quantification of binding at the therapeutic target and anxiety-related behavioral

responses stereotypical of the therapeutic efficacy of this model antidepressant. In

the Valenti et al. [ 53 ] study, adult male fathead minnow were exposed via aqueous

exposure to sertraline for 21 days. Fish plasma concentrations were accurately pre-

dicted from water exposures when pH influences on ionization and lipophilicitywere considered [ 29, 52, 54 ]. When these plasma levels in fish exceeded the human

therapeutic dose (C max

) of sertraline, binding to the serotonin reuptake transporter

and antianxiety behavior were significantly affected [ 53 ]. The AOP approach was

recently proposed by Ankley et al. [ 55 ] for linking molecular initiation events, such

as those related to pharmaceutical interactions with a target site (e.g., a receptor),

with cascading events leading to adverse outcomes at the individual and population

level, which can be used as measures of effect in risk assessments. As demonstrated

by Valenti et al. [ 53 ], linking predictions of uptake from surface waters to fish

plasma with conceptual AOP models appear to represent a sound foundation fromwhich potentially hazardous human pharmaceuticals may be identified.

Probabilistic hazard assessment approaches, which are commonly used to sup-

port environmental and public health decision making, can use existing mammalian

pharmacological safety data to develop predictive models for various parameters

[ 41 ]. These predictive tools can support prioritization activities for testing hypoth-

eses regarding pharmacological parameters of various drug classes or chemical

specific computational attributes that may result in hazards to wildlife [ 41 ]. For

example, Table 2 presents the minimum and maximum values and 10th, 50th and

90th centiles of probabilistic pharmaceutical distributions (PPD) of molecularweight, logP, acute LD

50 , C

max , acute to therapeutic ratio margin of safety analog

(LD50

/C max

; see [ 41 ]), clearance rate, half-life of elimination, apparent volume of

distribution (V d ), and the aqueous effect threshold (AqET; see [ 52 ]) based on data

from hundreds of pharmaceuticals. PPD approaches can be used to predict the


18/302


likelihood of encountering another therapeutic with attributes of interest. To illus-

trate the utility of PPD analyses, Fig. 2 depicts a PPD for V d . Briefly, V

d data were

ranked and converted to probability percentages then plotted against respective

probability ranks on a log-probability scale; centiles were determined by regression

(see [ 30 ] for a complete description of methods). Using this approach, we predict

that 10% or less of all pharmaceuticals would have V d values of 0.15 L/kg. In Fig. 3 ,

we extend the PPD assessment to predict the likelihood of encountering a pharma-

ceutical in surface waters exceeding the AqET value, which is based here on the

specific assumptions of Huggett et al.’s [ 47 ] plasma model. For example, 10% of allpharmaceuticals are predicted to result in internal fish plasma concentrations equal-

ing the human C max

value at or below an environmentally relevant surface water

concentration of 29 ng/L (Fig. 3 , Table 2 ).

Based on the current state of the science, it appears critical to develop an advanced

understanding of the risks associated with human pharmaceuticals in the environ-

ment. In Chaps. 6 and 7 , Lattier et al. consider mechanistic characteristics of drugs

for reconstructing environmental exposure scenarios and Brain and Brooks provide

perspectives for incorporating non-standard endpoints in environmental risk assess-

ments, respectively. In Chap. 8 , Williams and Brooks examine human health riskassessment considerations for environmental exposures to therapeutics. When the

outcome of an environmental risk assessment identifies unacceptable risks to wildlife

or humans, risk management decisions and practices serve as interventions to

protect public health and the environment. In the case of pharmaceuticals and other

Apparent Volume of Distribution (L/kg)

10-3 10-2 10-1 100 101 102 103 104

P e r c e n t R a n k

0.01

0.1

1

10

30

50

70

90

99

99.9

99.99

Fig. 2 Probabilistic pharmaceutical distribution of apparent volume of distribution (L/kg) for 944

pharmaceuticals. Reference lines relate to the 10th, 50th and 90th centiles (Table 2 ), which corre-

spond to 0.15, 1.03, and 6.96 L/kg, respectively. For example, apparent volume of distribution is

predicted by this model to be at or above 6.96 L/kg for 10% of all pharmaceuticals

http://dx.doi.org/10.1007/978-1-4614-3473-3_6http://dx.doi.org/10.1007/978-1-4614-3473-3_7http://dx.doi.org/10.1007/978-1-4614-3473-3_8http://dx.doi.org/10.1007/978-1-4614-3473-3_8http://dx.doi.org/10.1007/978-1-4614-3473-3_7http://dx.doi.org/10.1007/978-1-4614-3473-3_6


19/302


contaminants in treated wastewater effluents, a number of treatment approaches,

including appropriately designed and maintained constructed wetlands [ 56 ], appear

viable for supporting risk management of indirect and direct potable water reuse.

In this volume, Chaps. 9 and 10 examine timely issues related to environmental risk

management. In Chap. 9 , Gerrity and Snyder examine the available information

related to the efficacy of various wastewater and drinking water treatment technolo-

gies for human pharmaceuticals. In Chap. 10 , Stoddard and Huggett conclude this

volume with an interesting perspective on pharmaceutical take back programs,which promise to divert unused medications from down the drain discharges and

drug abuse by and poisonings of unintended users.

Lessons learned from human pharmaceuticals in the environment will continue to

advance our understanding of the environmental risks of chemicals. For example, a

number of organic contaminants are chiral, which remains an important environmental

consideration because fate and effects often differ among enantiomers [ 57 ]. Herein,

studies of chiral pharmaceuticals have advanced our understanding of risks posed by

other chiral chemicals [ 58 ]. Similarly, many environmental contaminants, including

metabolites and degradates, are weak acids and weak bases. Because site-specific pHinfluences environmental fate, uptake and toxicity, the study of ionizable therapeutics

(~70% of all drugs are weak bases) has advanced our understandings of the impacts of

climatic changes on bioaccumulation and toxicity of moderately polar and ionizable

chemicals [ 59, 60 ]. Interestingly, lessons learned from the study and design of less-toxic

Aqueous Effect Threshold (mg/L)

10-11 10-9 10-7 10-5 10-3 10-1 101 103 105 107 109

P e r c e n t R a n k

0.01

0.1

1

10

30

50

70

90

99

99.9

99.99

Fig. 3 Probabilistic pharmaceutical distribution of aqueous effect threshold (AqET; mg/L) for 831

pharmaceuticals. Reference lines relate to the 10th, 50th, and 90th centiles (Table 2 ), which cor-

respond to 29 ng/L, 44.6 m g/L, and 66.4 mg/L, respectively. For example, an aquatic concentration

leading to a plasma concentration in fish above the mammalian C max

value is predicted by the

AqET model to be at or below 29 ng/L for 10% of all pharmaceuticals

http://dx.doi.org/10.1007/978-1-4614-3473-3_9http://dx.doi.org/10.1007/978-1-4614-3473-3_10http://dx.doi.org/10.1007/978-1-4614-3473-3_9http://dx.doi.org/10.1007/978-1-4614-3473-3_10http://dx.doi.org/10.1007/978-1-4614-3473-3_10http://dx.doi.org/10.1007/978-1-4614-3473-3_9http://dx.doi.org/10.1007/978-1-4614-3473-3_10http://dx.doi.org/10.1007/978-1-4614-3473-3_9


20/302


pharmaceuticals, often described as benign by design [ 61 ], can be extended to advance

green chemistry principles by developing sustainable molecular design guidelines for

reducing the toxicity of other industrial contaminants [ 62, 63 ]. To the fields of aquatic

toxicology and environmental risk assessment in particular, understanding the toxicity

of human pharmaceuticals in the environment is beginning to advance our understand-

ing of toxicity pathways. To date, relatively few toxicity pathways have been defined in

ecological systems, but hundreds of pharmaceuticals targets are evolutionarily con-

served across the various kingdoms. Developing an understanding of pharmaceutical

MOAs and associated AOPs will improve prospective and retrospective diagnosis and

management of environmental risks posed by industrial contaminants. Clearly a num-

ber of timely research questions remain unanswered [ 21 ].

References

1. Postel S (2010) Water: adapting to a new normal. In: Heinberg R, Lerch D (eds) The Post

Carbon Reader: managing the 21st Century’s Sustainability Crises. Watershed Media/

University of California Press, California

2. Fish on Prozac. http://news.sciencemag.org/sciencenow/2003/11/04-01.html

3. Brooks BW, Chambliss CK, Stanley JK, Ramirez AJ, Banks KE, Johnson RD, Lewis RJ

(2005) Determination of select antidepressants in fish from an effluent-dominated stream.

Environ Toxicol Chem 24:464–469

4. Male fish becoming female? Researchers worry about estrogen and pollutants in the water.http://www.msnbc.msn.com/id/6436617/ns/nightly_news/t/male-fish-becoming-female

5. Woodling JD, Lopez EM, Maldonado TA, Norris DO, Vajda AM (2006) Intersex and other

reproductive disruption of fish in wastewater effluent dominated Colorado streams. Comp

Biochem Phys Part C 144:10–15

6. Drugs found in drinking water. http://hosted.ap.org/specials/interactives/pharmawater_site

7. Benotti MJ, Trenholm RA, Vanderford BJ, Holady JC, Stanford BD, Snyder SA (2009)

Pharmaceuticals and endocrine disrupting compounds in U.S. drinking water. Environ Sci

Technol 43:597–603

8. India’s drug problem. http://www.nature.com/news/2009/090204/full/457640a.html

9. Colburn T, Dumanoski D, Myers JP (1996) Our stolen future. Dutton, Peguin Books, New York

10. Carson R (1962) Silent spring. Houghton Mifflin Company, New York11. Ankley GT, Brooks BW, Huggett DB, Sumpter JP (2007) Repeating history: pharmaceuticals

in the environment. Environ Sci Technol 41:8211–8217

12. Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, Foster PM,

Gray CL, Gray LE (2008) Fifteen years after “Wingspread”—environmental endocrine dis-

rupters and human and wildlife health: where we are today and where we need to go. Toxicol

Sci 105:235–259

13. Desbrow C, Routledge E, Brighty G, Sumpter J, Waldock M (1998) Identification of estro-

genic chemicals in STW effluent. 1. Chemical fractionation and in vitro biological screening.

Environ Sci Technol 32:1549–1558

14. Arcand-Hoy L, Nimrod AC, Benson WH (1998) Endocrine-modulating substances in the envi-

ronment: estrogenic effects of pharmaceutical products. Int J Toxicol 17:139–15815. Halling-Sorensen B, Nielsen SN, Lanzky PF, Ingerslev F, Lutzhoft HCH, Jorgensen SE (1998)

Occurrence, fate and effects of pharmaceutical substances in the environment—a review.

Chemosphere 36:357–394

16. Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Water

Res 32:3245–3260

http://news.sciencemag.org/sciencenow/2003/11/04-01.htmlhttp://www.msnbc.msn.com/id/6436617/ns/nightly_news/t/male-%ef%ac%81sh-becoming-femalehttp://hosted.ap.org/specials/interactives/pharmawater_sitehttp://www.nature.com/news/2009/090204/full/457640a.htmlhttp://www.nature.com/news/2009/090204/full/457640a.htmlhttp://hosted.ap.org/specials/interactives/pharmawater_sitehttp://www.msnbc.msn.com/id/6436617/ns/nightly_news/t/male-%ef%ac%81sh-becoming-femalehttp://news.sciencemag.org/sciencenow/2003/11/04-01.html


21/302


17. Daughton CG, Ternes TA (1999) Pharmaceuticals and personal care products in the environ-

ment: agents of subtle change? Environ Health Perspect 107(suppl 6):907–938

18. Williams RT (ed) (2005) Human pharmaceuticals: assessing impacts on aquatic ecosystems.

SETAC Press, Pensacola, Florida

19. Crane M, Barrett K, Boxall A (eds) (2008) Veterinary medicines in the environment. SETAC

Press, Pensacola, Florida

20. Brooks BW, Huggett DB, Boxall ABA (2009) Pharmaceuticals and personal care products:

research needs for the next decade. Environ Toxicol Chem 28:2469–2472

21. Boxall ABA, Rudd M, Brooks BW, Caldwell D, Choi K, Hickmann S, Innes E, Ostapyk K,

Staveley J, Verslycke T, Ankley GT, Beazley K, Belanger S, Berninger JP, Carriquiriborde P,

Coors A, DeLeo P, Dyer S, Ericson J, Gagne F, Giesy JP, Gouin T, Hallstrom L, Karlsson M,

Larsson DGJ, Lazorchak J, Mastrocco F, McLaughlin A, McMaster M, Meyerhoff R, Moore

R, Parrott J, Snape J, Murray-Smith R, Servos M, Sibley PK, Straub JO, Szabo N, Tetrault G,

Topp E, Trudeau VL, van Der Kraak G (2012) Pharmaceuticals and personal care products in

the environment: what are the big questions? Environ Health Perspect (in press)

22. Kolpin DW, Furlong ET, Meyer MT, Thurman EM, Zaugg SD, Barber LB, Buxton HT (2002)Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams,

1999–2000: a national reconnaissance. Environ Sci Technol 36:1202–1211

23. Monteiro SC, Boxall ABA (2010) Occurrence and fate of human pharmaceuticals in the envi-

ronment. Rev Environ Contam Toxicol 202:53–154

24. Nordlander I, Johnsson H, Osterdahl B (1987) Oxytetracycline residues in rainbow trout ana-

lyzed by a rapid HPLC method. Food Addit Contam 4:291–296

25. Capone DG, Weston DP, Miller V, Shoemaker C (1996) Antibacterial residues in marine sedi-

ments and invertebrates following chemotherapy in aquaculture. Aquaculture 145:55–75

26. Boxall ABA, Johnson P, Smith EJ, Sinclair CJ, Stutt E, Levy LS (2006) Uptake of veterinary

medicines from soils into plants. J Agric Food Chem 54:2288–2297

27. Larsson DGJ, Adolfsson-Erici M, Parkkonen J, Pettersson M, Berg AH, Olsson PE, Forlin L(1999) Ethinyloestradiol—an undesired fish contraceptive? Aquat Toxicol 45:91–97

28. Ramirez AJ, Brain RA, Usenko S, Mottaleb MA, O’Donnell JG, Stahl LL, Wathen JB, Snyder

BD, Pitt JL, Perez-Hurtado P, Dobbins LL, Brooks BW, Chambliss CK (2009) Occurrence of

pharmaceuticals and personal care products (PPCPs) in fish: results of a national pilot study in

the U.S. Environ Toxicol Chem 28:2587–2597

29. Daughton CG, Brooks BW (2011) Active pharmaceuticals ingredients and aquatic organisms.

In: Meador J, Beyer N (eds) Environmental contaminants in wildlife: interpreting tissue con-

centrations, 2nd edn. Taylor and Francis, Boca Raton, pp 281–341

30. Zhang X, Oakes KD, Cui S, Bragg L, Servos MR, Pawliszyn J (2010) Tissue-specific in vivo

bioconcentration of pharmaceuticals in rainbow trout (Oncorhynchus mykiss) using space-

resolved solid-phase microextraction. Environ Sci Technol 44:3417–342231. Paterson G, Metcalfe CD (2008) Uptake and depuration of the anti-depressant fluoxetine by

the Japanese medaka (Oryzias latipes). Chemosphere 74:125–130

32. Nallani G, Paulos P, Vanables B, Constantine L, Huggett DB (2011) Bioconcentration of

Ibuprofen in Fathead minnow (Pimephales promelas ) and Channel catfish ( Ictalurus puncta-

tus ). Chemosphere 84:1371–1377

33. Nallani G, Paulos P, Vanables B, Constantine L, Huggett DB (2011) Tissue specific uptake and

bioconcentration of the oral contraceptive, Norethindrone, in two freshwater fishes. Arch

Environ Contam Toxicol 62(2):306–313

34. Smith EM, Chu S, Paterson G, Metcalfe CD, Wilson JY (2010) Cross-species comparison of

fluoxetine metabolism with fish liver microsomes. Chemosphere 79:26–32

35. Gomez C, Constantine L, Moen M, Vaz A, Huggett DB (2010) The influence of gill and livermetabolism on the predicted bioconcentration in fish. Chemosphere 81:1189–1195

36. Gomez CF, Constantine L, Moen M, Vaz A, Wang W, Huggett DB (2011) Ibuprofen metabolism in the

liver and fill of rainbow trout, Oncorhynchus mykiss. Bull Environ Contam Toxicol 86:247–251

37. Schultz MM, Painter MM, Bartell SE, Logue A, Furlong ET, Werner SL, Shoenfuss HL (2011)

Selective uptake and biological consequences of environmentally relevant antidepressant phar-

maceutical exposures on male fathead minnows. Aquat Toxicol 104:38–47


22/302


38. Nakamura Y, Yamamoto H, Sekizawa J, Kondo T, Hirai N, Tatarako N (2008) The effects of

pH on fluoxetine in Japanese medaka (Oryzias latipes ): acute toxicity in fish larvae and bioac-

cumulation in juvenile fish. Chemosphere 70:865–873

39. Zhou SN, Oakes KD, Servos MR, Pawliszyn J (2008) Application of solid-phase microextrac-

tion for in vivo laboratory and field sampling of pharmaceuticals in fish. Environ Sci Technol

42:6073–6079

40. Environmental Defense Fund (1997) Toxic ignorance: the continuing absence of basic health

testing for top-selling chemicals in the United States. Environmental Defense Fund, New York

41. Berninger JP, Brooks BW (2010) Leveraging mammalian pharmaceutical toxicology and

pharmacology data to predict chronic fish responses to pharmaceuticals. Toxicol Lett

193:69–78

42. Brausch JM, Connors KA, Brooks BW, Rand GM (2012) Human pharmaceuticals in the

aquatic environment: a critical review of recent toxicological studies and considerations for

toxicity testing. Rev Environ Contam Toxicol 218:1–99

43. Brooks BW, Riley TM, Taylor RD (2006) Water quality of effluent-dominated stream ecosys-

tems: ecotoxicological, hydrological, and management considerations. Hydrobiologia556:365–379

44. Seiler JP (2002) Pharmacodynamic activity of drugs and ecotoxicology: can the two be con-

nected? Toxicol Lett 131:105–115

45. Huggett DB, Brooks BW, Peterson B, Foran CM, Schlenk D (2002) Toxicity of select beta-

adrenergic receptor blocking pharmaceuticals (b -blockers) on aquatic organisms. Arch Environ

Contamin Toxicol 42:229–235

46. Brooks BW, Foran CM, Richards S, Weston JJ, Turner PK, Stanley JK, Solomon K, Slattery M,

La Point TW (2003) Aquatic ecotoxicology of fluoxetine. Toxicol Lett 142:169–183

47. Huggett DB, Cook JC, Ericson JF, Williams RT (2003) A theoretical model for utilizing mammalian

pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish.

Hum Ecol Risk Assess 9:1789–179948. Fitzsimmons PN, Fernandez JD, Hoffman AD, Butterworth BC, Nichols JW (2001) Branchial

elimination of superhydrophobic organic compounds by rainbow trout (Oncorhynchus mykiss ).

Aquat Toxicol 55:23–34

49. Brown JN, Paxeus N, Forlin L, Larsson DGJ (2007) Variations in bioconcentration of human

pharmaceuticals from sewage effluents into fish blood plasma. Environ Toxicol Pharmacol

24:267–274

50. Fick J, Lindberg RH, Parkkonen J, Arvidsson B, Tysklind M, Larsson DGJ (2010) Therapeutic

levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout

exposed to treated sewage effluents. Environ Sci Technol 44:2661–2666

51. Fick J, Lindberg RH, Tysklind M, Larsson DGJ (2010) Predicted critical environmental con-

centrations for 500 pharmaceuticals. Regul Toxicol Pharmacol 58:516–52352. Berninger JP, Du B, Connors KA, Eytcheson SA, Kolkmeier MA, Prosser KN, Valenti TW,

Chambliss CK, Brooks BW (2011) Effects of the antihistamine diphenhydramine to select

aquatic organisms. Environ Toxicol Chem 30:2065–2072

53. Valenti TV, Gould GG, Berninger JP, Connors KA, Keele NB, Prosser KN, Brooks BW (2012)

Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (SSRI) sertraline

decrease serotonin reuptake transporter binding and shelter seeking behavior in adult male

fathead minnows. Environ Sci Technol 46:2427–2435

54. Valenti TW, Perez Hurtado P, Chambliss CK, Brooks BW (2009) Aquatic toxicity of sertraline

to Pimephales promelas at environmentally relevant surface water pH. Environ Toxicol Chem

28:2685–2694

55. Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR,Nichols JW, Russom CL, Schmieder PK, Serrano JA, Tietge JE, Villeneuve DL (2010) Adverse

outcome pathways: a conceptual framework to support ecotoxicology research and risk assess-

ment. Environ Toxicol Chem 29:730–741


23/302


56. Mokry L, Brooks BW, Chambliss CK, Knight R, Keller C, Sedlak DL (2011) Evaluate wetland

systems for treated wastewater performance to meet competing effluent quality goals.

WateReuse Research Foundation, Alexandria, VA. 153 p

57. Garrison AW (2006) Probing the enantioselectivity of chiral pesticides. Environ Sci Technol

40:16–23

58. Stanley JK, Brooks BW (2009) Perspectives on ecological risk assessment of chiral com-

pounds. Integr Environ Assess Manag 5:364–373

59. Valenti TW, Taylor JT, Back JA, King RS, Brooks BW (2011) Influence of drought and total

phosphorus on diel pH in wadeable streams: implications for ecological risk assessment of

ionizable contaminants. Integr Environ Assess Manag 7:636–647

60. Brooks BW, Valenti TW, Cook-Lindsay BA, Forbes MG, Scott JT, Stanley JK, Doyle RD

(2011) Influence of Climate change on reservoir water quality assessment and management:

effects of reduced inflows on diel pH and site-specific contaminant hazards. In: Linkov I,

Bridges TS (eds) Climate: global change and local adaptation. NATO science for peace and

security series C: environmental security. Springer, New York, pp 491–522

61. Kümmerer K (2007) Sustainable from the very beginning: rational design of molecules by lifecycle engineering as an important approach for green pharmacy and green chemistry. Green

Chem 9:899–907

62. Voutchkova AM, Kostal J, Steinfeld JB, Emerson JW, Brooks BW, Anastas P, Zimmerman JB

(2011) Towards rational molecular design: derivation of property guidelines for reduced acute

aquatic toxicity. Green Chem 13:2373–2379

63. Voutchkova AM, Kostal J, Connors KA, Brooks BW, Anastas P, Zimmerman JB (2012) Towards

rational molecular design for reduced chronic aquatic toxicity. Green Chem 14:1001–1008

64. Fatta D, Nikolaou A, Achilleos A, Meric S (2007) Analytical methods for tracing pharmaceu-

tical residues in water and wastewater. Trends Anal Chem 26:515–533

65. Gros M, Petrovic M, Barcelo D (2006) Multi-residue analytical methods using LC-tandem MS

for the determination of pharmaceuticals in environmental and wastewater samples: a review.Anal Bioanal Chem 386:941–952

66. Hao C, Clement R, Yang P (2007) Liquid chromatography–tandem mass spectrometry of bio-

active pharmaceutical compounds in the aquatic environment a decade’s activities. Anal

Bioanal Chem 387:1247–1257

67. Hernando MD, Gomez MJ, Aguera A, Fernandez-Alba AR (2007) LC-MS analysis of basic

pharmaceuticals (beta-blockers and anti-ulcer agents) in wastewater and surface water. Trends

Anal Chem 26:581–594

68. Hernandez J, Sancho JV, Ibañez M, Guerrero C (2007) Antibiotic residue determination in

environmental waters by LC-MS. Trends Anal Chem 26:466–485

69. Wong CS, MacLeod SL (2009) JEM spotlight: recent advances in analysis of pharmaceuticals

in the aquatic environment. J Environ Monit 11:923–93670. Kim SC, Carlson K (2005) LC–MS2 for quantifying trace amounts of pharmaceutical com-

pounds in soil and sediment matrices. Trends Anal Chem 24:635–644

71. O’Connors S, Aga DS (2007) Analysis of tetracycline antibiotics in soil: advances in extrac-

tion, clean-up, and quantification. Trends Anal Chem 26:456–465

72. Buchberger WW (2007) Novel analytical procedures for screening of drug residues in water,

waste water, sediment and sludge. Anal Chim Acta 593:129–139

73. Petrovic M, Hernando MD, Diaz-Cruz MS, Barcelo D (2005) Liquid chromatography–tandem

mass spectrometry for the analysis of pharmaceutical residues in environmental samples: a

review. J Chromatogr A 1067:1–14

74. Giger W (2009) Hydrophilic and amphiphilic water pollutants using advanced analytical

methods for classic and emerging contaminants. Anal Bioanal Chem 393:37–4475. Richardson S (2009) Water analysis: emerging contaminants and current issues. Anal Chem

81:4645–4677

76. Barcelo D, Petrovic M (2007) Challenges and achievements of LC-MS in environmental

analysis: 25 years on. Trends Anal Chem 26:2–11


24/302


77. Hao C, Zhao X, Yang P (2007) GC-MS and HPLC-MS analysis of bioactive pharmaceuticals

and personal-care products in environmental matrices. Trends Anal Chem 26:569–580

78. Morley MC, Snow DD, Cecrle C, Denning P, Miller L (2006) Emerging chemicals and analyti-

cal methods. Water Environ Res 78:1017–1053

79. Kot-Wasik A, Debska J, Namiesnik J (2007) Analytical techniques in studies of the environ-

mental fate of pharmaceuticals and personal-care products. Trends Anal Chem 26:557–568

80. Richardson S (2008) Environmental mass spectrometry: emerging contaminants and current

issues. Anal Chem 80:4373–4402

81. Rubio S, Perez-Bendito D (2009) Recent advances in environmental analysis. Anal Chem 81:

4601–4622

82. Perez S, Barcelo D (2007) Application of advanced MS techniques to analysis of human and

microbial metabolites of pharmaceuticals in the aquatic environment. Trends Anal Chem 26:

494–514

83. Petrovic M, Barcelo D (2007) LC-MS for identifying photodegradation products of pharma-

ceuticals in the environment. Trends Anal Chem 26:486–493

84. Radjenovic J, Petrovic M, Barcelo D (2007) Advanced mass spectrometric methods applied tothe study of fate and removal of pharmaceuticals in wastewater treatment. Trends Anal Chem

26:1132–1144

85. Kosjek T, Heath E, Petrovic M, Barcelo D (2007) Mass spectrometry for identifying pharma-

ceutical biotransformation products in the environment. Trends Anal Chem 26:1076–1085

86. Kostopoulou M, Nikolaou A (2008) Analytical problems and the need for sample preparation

in the determination of pharmaceuticals and their metabolites in aqueous environmental matri-

ces. Trends Anal Chem 27:1023–1035

87. Escandar GM, Faber NM, Goicochea HC, Muñoz de la Peña A, Olivieri AC, Poppi RJ (2007)

Second- and third-order multivariate calibration data, algorithms and applications. Trends

Anal Chem 26:752–765

88. Galera MM, Gil Garcia MD, Goicochea HC (2007) The Application to wastewaters ofchemometric approaches to handling problems of highly complex matrices. Trends Anal Chem

26:1032–1042

89. Lambropoulou DA, Konstantinou IK, Albanis TA (2007) Recent developments in headspace

microextraction techniques for the analysis of environmental contaminants in different matri-

ces. J Chromatogr A 1152:70–96

90. Pavloivc DM, Babic S, Horvat AJM, Kastelan-Macan M (2007) Sample preparation in analy-

sis of pharmaceuticals. Trends Anal Chem 26:1062–1075

91. Pichon V, Chapuis-Hugon F (2008) Role of molecularly imprinted polymers for selective

determination of environmental pollutants—a review. Anal Chim Acta 622:48–61

92. Rodriguez-Mozaz S, Lopez de Alda MJ, Barcelo D (2007) Advantages and limitations of on-

line solid phase extraction coupled to liquid chromatography–mass spectrometry technologiesversus biosensors for monitoring of emerging contaminants in water. J Chromatogr A 1152:

97–115

93. Soderstrom H, Lindberg RH, Fick J (2009) Strategies for monitoring the emerging polar

organic contaminants in water with emphasis on integrative passive sampling. J Chromatogr

A 1216:623–630

94. Wardencki W, Curylo J, Namiesnik J (2007) Trends in solventless sample preparation tech-

niques for environmental analysis. J Biochem Biophys Methods 70:275–288

95. Perez S, Barcelo D (2008) Applications of LC-MS to quantitation and evaluation of the envi-

ronmental fate of chiral drugs and their metabolites. Trends Anal Chem 27:836–846

96. Ramirez AJ, Mottaleb MA, Brooks BW, Chambliss CK (2007) Analysis of pharmaceuticals in

fish tissue using liquid chromatography—tandem mass spectrometry. Anal Chem 79:3155–3163


25/302

17B.W. Brooks and D.B. Huggett (eds.), Human Pharmaceuticals in the Environment:Current and Future Perspectives, Emerging Topics in Ecotoxicology 4,DOI 10.1007/978-1-4614-3473-3_2, © Springer Science+Business Media, LLC 2012

Introduction

An overview is given on environmental risk assessment for pharmaceuticals (ERA),with a description of the current regulatory requirements for human pharmaceuti-cals ERA in Europe and the USA as well as developments worldwide. In addition,further developments on national levels concerning the environmental safety ofpharmaceuticals are presented. Also, a short comparison with international veteri-nary pharmaceuticals guidelines and with biocides ERA is given.

As long as human population density is low and excreta are spread diffusely overa large area, no significant levels of PAS or metabolites are expected in the environ-ment. But when population density increases, when excreta collect in sewage andthe latter is discharged, after wastewater treatment or not, to receiving waters, mea-surable to significant concentrations in surface waters may be reached. With strongpopulation growth in industrialised societies from the nineteenth century onward,with sewage collection systems in the growing cities and with the increase in thenumber of pharmaceutical companies and their biologically active products, a risein environmental concentrations of at least certain PAS followed during the pastcentury. A parallel development in analytical methods and power, expressed asconstantly decreasing limits of detection and quantitation, inevitably led to determi-nations of PAS in environmental matrices.

J.O. Straub (*) F.Hoffmann-La Roche Ltd, Group SHE,LSM 49/2.033, Basle CH-4070, Switzerland

e-mail: [email protected]. HutchinsonCEFAS Weymouth Laboratory, Centre for Environment, Fisheries and Aquaculture Sciences,The Nothe, Barrack Road, Weymouth, Dorset DT4 8UB, UKe-mail: [email protected]

Environmental Risk Assessment for Human

Pharmaceuticals: The Current State

of International Regulations

Jürg Oliver Straub and Thomas H. Hutchinson


26/302

18 J.O. Straub and T.H. Hutchinson

The first analytical detections of PAS and metabolites in environmental mediaare reported from the USA in the 1970s [ 33, 37 ], where among others salicylicacid, the main metabolite of acetylsalicylic acid was detected in sewage workseffluent. These initial detections initiated a rapidly growing list of similar publica-tions and reviews covering sewage treatment effluent, surface, estuarine, marine,ground and tap water over the following decades (e.g. Richardson and Bowron[ 64 ] , Aherne and Briggs [ 1 ], Ayscough et al. [ 4 ] and Thomas and Hilton [ 77 ] in theUK; Heberer et al. [ 35 ] and Ternes et al. [ 73 ] in Germany; Halling-Sørensen et al.[ 34 ] in Denmark; Buser et al. [ 10 ] and Tixier et al. [ 77 ] in Switzerland; Belfroidet al. [ 6 ] in the Netherlands; Stumpf et al. [ 72 ] in Brazil; Zuccato et al. [ 84 ] andCalamari et al. [ 11 ] in Italy; Farré et al. [ 28 ] and Fernández et al. [ 29 ] in Spain;Kolpin et al. [ 48 ] and Barnes et al. [ 5 ] in the USA; Metcalfe et al. [ 54 ] in Canada;Vieno et al. [ 81 ] in Finland; Nakada et al. [ 57 ] in Japan; Rabiet et al. [ 63 ] in France;

Kim et al. [ 47 ] in South Korea). Note this is not meant to be a complete list butrather an illustration of the worldwide increase in publications in the 1990s and2000s. Again, the scope of detections widened with massively refined analyticalinstruments and methods.

In parallel to these ubiquitous detections in environmental media, the question ofpossible adverse effects caused by PAS to environmental organisms and ecosystemsalso gained importance. Initial environmental risk assessments (ERAs), comparingenvironmental concentrations with known effects, began in the 1980s. The concernsabout environmental safety of PAS, alone and in particular in combinations, strongly

increased with accruing evidence for widespread endocrine disruption in wild fish[ 44 ], in particular downstream of sewage treatment works effluents and also withexperimental adverse effects seen with a few PAS at very low concentrations (e.g.[ 19, 30, 43 ]), which in some cases were close to or within the range of measuredenvironmental concentrations (MECs). In parallel, the use of PAS or similar sub-stances has played an important role in other areas of aquatic research, includingaquaculture [ 31, 40 ] and marine antifoulant paints [ 38, 50, 61 ].

In view of mounting evidence for widespread environmental exposure and poten-tial or probable environmental effects of PAS, enquiries and investigations into

environmental hazards and risks due to PAS began in the 1980s (e.g. [ 1, 18, 34, 36, 46, 65, 78 ]). In parallel to these often government-sponsored investigations, thenecessity for and development of formal ERAs specifically for PAS (pharmaceuti-cals ERA or PERA) was recognised by regulators on both sides of the Atlantic,which led to legal requirements and, with some delay, to guidelines for such PERAsas part of the registration dossier from the 1990s onwards. Formal guidelines weredeveloped and published in 1998 in the USA and in 2006 in the European Union(EU). In other countries, PERAs are requested (e.g. Australia) or formal own guidelinesare in the making (Canada, Japan). In addition, Sweden led the way with a system

for the ERA of “old” PAS already on the market. But even beyond the formalrequirements for PERAs in the context of registration, PAS in the environment (PIE)may be the subject of other legislation than registration, which, however, may stillrequire some kind of ERA. These developments and current states will be outlined inthe following paragraphs.


27/302

19Current State of Regulations for Human Pharmaceuticals ERA

Current State of PERA Regulation in Various

Regions or Countries

PERA started in the USA and EU in the 1980s or early 1990s. Much of the method-ology seems to derive from pesticides ERA, which came into focus and developedappropriate methodologies earlier than pharmaceuticals in general. All of the ERAprocedures have in common a comparison between predicted (or measured) environ-mental concentrations (PECs or MECs) with predicted no effect concentrations(PNECs), both per environmental compartment under consideration. Such compart-ments may be wastewater treatment, surface waters, sediments, groundwaters, tidaland coastal/marine waters, soils (through landspreading of surplus sewage sludge,called biosolids in North American terminology) and, rarely, the atmosphere. PECs

are derived from either predicted use or maximum daily use multiplied by a defaultuse or penetration factor in the population, integrating human metabolism and deple-tion during sewage treatment or in the environment, sorption and distribution to otherenvironmental compartments, dilution and advection (off-transport by the medium) inthe receiving compartments. PNECs are mostly derived from either acute or chronicecotoxicity tests, normally with standard organism groups representative for the com-partment, by dividing by assessment factors (AFs) which are dependent on the char-acter and number of ecotoxicity results available. In higher tiers of the ERA, the abovedeterministic procedure using AFs can be replaced by probabilistic methodology,

where the distributional characteristics of a number of ecotoxicity test results(normally at least ten chronic datapoints) are used to derive a PNEC. PECs and PNECsare compared per compartment, in general through forming the PEC/PNEC ratio.If this ratio is


28/302


assessments (EAs in US legal terminology) within the US Food and Drugs legislation(21 CFR 25; current version available at http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25 ). By this, “all applications or petitionsrequesting Agency action must be accompanied by either an EA or a claim of categor-ical exclusion; failure to submit one or the other is sufficient grounds for refusing tofile or approve the application” (cited from “Environmental Impact Review at CDER”,http://www.fda.gov/AboutFDA/CentersOf fices/CDER/ucm088969.html). In 1998 theUS Center for Drug Evaluation and Research (CDER) and the Center for BiologicsEvaluation and Research (CBER) within the US Food and Drug Administration pub-lished a “Guidance for Industry, Environmental Assessment of Human Drug andBiologics Applications”, revision 1 [ 14 ], which is still current today.

The Guidance describes in which cases an EA can be waived and how to proceedwith an EA in the remainder. Waivers, the so-called categorical exclusions, may be

invoked in the following cases:

If the application does not increase the use of active moiety (i.e. in case of exten-•sions or additional applications by third parties for PAS already on the market).If the application may lead to increased use but the estimated concentration of•the AS at the point of entry into the environment is less than 1 part per billion(ppb). This means that the entry into the environment concentration (EIC) of aparticular PAS from US publicly owned treatment works (POTWs) must bebelow 1 m g/L, discounting all metabolism; calculating back from an EIC of

1m

g/L and the average annual total effluent of all POTWs results in a maximumannual amount of approximately 44 metric tonnes of PAS per year for the wholecontinental USA, based on daily POTW inflow data given in the Guidance ([ 14 ];p 4). Hence, if the predicted annual use of a new PAS is below 44 tonnes/annumthere is no need for an EA, except if the applicant has information to suggest thatthe use of even a lesser quantity may “significantly affect the quality of thehuman environment” ([ 14 ]; p 3).For biological PAS if their use will not lead to significant concentrations in the•environment.For investigational new drugs still under development in clinical research.•For specific biological products for blood or plasma transfusion.•

In all other cases, the applicant needs to prepare an EA following a tiered, step-wise approach that follows the course of a PAS from human excretion into theenvironment. Hence, in a first basic step , if there is experimental evidence that anew PAS is rapidly depleted, e.g. through biodegradation in a POTW, and not inhib-itory to microorganisms, the EA can be stopped and finalised with a Finding of NoSignificant Impact (FONSI). If the PAS is not rapidly depleted and if it is lipophilic(with an n -octanol/water distribution coefficient logD

OW ³ 3.5 at a relevant environ-

mental pH of approximately 7), suggesting bioaccumulation, the applicant shouldinitiate chronic testing in tier 3; note the tier numbering is given according to theGuidance [ 14 ]. Further details as to depletion (degradation, hydrolysis or parti-tioning to other environmental compartments) and to interpretation of these fateprocesses are given.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088969.htmlhttp://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088969.htmlhttp://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088969.htmlhttp://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088969.htmlhttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=25


29/302


In all other cases, the effects testing starts with one acute test in tier 1. If the ratioof the 50% effect or 50% lethal concentration (EC50 or LC50) in this test dividedby the EIC or predicted (or expected in US terminology) environmental concentra-tion (PEC or EEC), whichever is higher, is ³ 1,000 and there were no adverse effectsobserved at the higher of EIC or EEC (termed maximum expected environmentalconcentration or MEEC), the EA can be stopped and finalised. This ratio corre-sponds to a margin of safety (MOS) in general ERA terminology. If there wereeffects at MEEC, the applicant should initiate chronic testing in tier 3.

If the tier 1 MOS is


30/302


(e.g. [ 55 ], for Delaware drinking waters). Within half a year starting from the firstAP report, according to the AP [ 3 ] site, a US Congressional Panel discussed moni-toring and potential impacts of micropollutants including PAS in environmentalwaters, which are currently not regulated by the US Environmental ProtectionAgency (EPA) either as a group or as single substances in the USA. The discussionseemed to focus mainly on potential human risks from PIE through water abstrac-tion, treatment and consumption as drinking water, but less on risks for environmen-tal organisms or ecosystems. Also, questions on PIE and the safety of PAS indrinking waters were raised in the US Senate Committee on Environment and PublicWorks ( http://epw.senate.gov/public/index.cfm , search for “pharmaceuticals” and“water”). Some investigations on potential human health risks from PIE via drink-ing water were published in the previous decade (e.g. [ 9, 12, 16, 17, 45, 67, 83, 84 ]),all of which have found no significant risks based on the available evidence.

In addition, on July 7, 2010, the Great Lakes Environmental Law Center and theNatural Resources Defense Council as petitioners submitted a “Citizen Petition” tothe US Food and Drugs Administration Commissioner. A Citizen Petition in the USis a legal means to challenge existing regulations. In this Citizen Petition concerningan amendment to the current US PERA Guidance [ 14 ], the repealing of the categori-cal exclusion threshold of 1 ppt (1 m g/L, corresponding to approximately 44 metrictonnes of PAS per annum) EIC is requested, “because the current regulation doesnot reflect a safe standard supported by current scientific information”. In case thethreshold for a categorical exclusion is indeed repealed, this would mean that nearly

all new human PAS would need an EA for registration.It will remain to be seen whether the parliamentary discussions and legal motions

in the USA will eventually have effects on US regulations, on PERA in general, onthe US PERA Guideline, possibly also for “old” PAS already on the market, or forthe regulation of water contaminants by the EPA.

PERA in the European Union

First requirements for PERA were laid down in EU Directive 93/39/EEC, whichasked to “give indications of any potential risks presented by the medicinal productto the environment”. The development of the PERA guideline in the EU took 13years in all, with several draft guidelines published during that time [ 68, 69 ]. In2006, the European Medicines Agency (EMA, London, UK; note that the formerabbreviation EMEA for European Medicines Evaluation Agency is not being usedany longer) published the first definitive Guideline for Environmental RiskAssessment of Human Medicines [ 26 ]. This guideline describes a tiered procedure,

from categorical exclusion or direct referral, to a simple, worst-case exposure esti-mation of a pharmaceutical active substance to the investigation of fate and effectsin sewage works and surface waters, up to a refined assessment for these or otherenvironmental compartments.

http://epw.senate.gov/public/index.cfmhttp://epw.senate.gov/public/index.cfmhttp://epw.senate.gov/public/index.cfm


31/302


A PERA is required for new registrations (Medicines AuthorisationApplication or MAA in EU terminology) and for all repeat registrations by thesame applicant, termed “variations” in the EU, that may lead to significantlyincreased environmental exposure to the PAS; note that “significant” is notdefined or quantified in this context. In the basic Phase 1 of the PERA, certaincategories of PAS are excluded from PERA (amino acids, proteins, peptides,carbohydrates, lipids, electrolytes, vaccines and herbal medicines), while otherPAS are directly referred to special ERA. Highly lipophilic PAS with a log K

OW

> 4.5 are directly referred to a persistence, bioaccumulation a

Documents

Human Pharmaceuticals in Environment